Transient genomic instability drives tumorigenesis through accelerated clonal evolution
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ABSTRACT:
PROVIDER: PRJNA679266 | ENA |
REPOSITORIES: ENA
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Project description:Abnormal numerical and structural chromosome content is frequently found in human cancer. However, the role of aneuploidy in tumor initiation and progression is poorly understood. To test the effect of aneuploidy on cancer development, we transiently induced chromosome instability (CIN) in mice by inducible overexpression of polo-like kinase 4 (PLK4), a master regulator of centrosome number. Short term increased PLK4 expression generated significant centrosome amplification and aneuploidy resulting in the formation of aggressive T cell lymphomas in mice with heterozygous inactivation of one p53 allele or accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphoma-initiating cells, as revealed by T cell receptor sequencing of tumor samples. Transient CIN produced a unique tumor karyotype containing triploid chromosomes 4, 5, 14, and 15, as determined by whole genome sequencing.
2021-06-14 | GSE161728 | GEO
Project description: Not available
| S-EPMC8336898 | biostudies-literature
Project description:Background and Aims: Telomere dysfunction can increase tumor initiation by induction of chromosomal instability, but initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. However, this concept has not been proven in vivo since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis (i) in a novel mouse model of inducible telomere dysfunction on a telomerase-proficient background, (ii) in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and (iii) in wild-type mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation and cancer cell proliferation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell cycle arrest and apoptosis in telomerase-deficient liver tumors. Together, these data provide the first in vivo evidence that transient telomere dysfunction during early and late stages of tumorigenesis can promote chromosomal instability and carcinogenesis in telomerase-proficient mice in the absence of additional genetic checkpoint defects at germline level. RNA from liver tumors derived from from DEN treated TTD+ mice TTD- mice and RNA from normal liver 48h-72h after doxycycline induced transient telomere dysfunction in TTD+ and TTD- liver were isolated and RNA was extracted. Agilent Mouse 4x44K v2 arrays were used. DNA from liver tumors and corrresponding kidney as control derived from from DEN treated TTD+ mice, TTD- mice and mTERC-/- G3 mice was isolated and extracted using Phenol/Chloroform. Agilent Mouse 4x44K and Mouse 1x244K arrays were used.
2012-03-30 | E-GEOD-36813 | biostudies-arrayexpress
Project description:Background and Aims: Telomere dysfunction can increase tumor initiation by induction of chromosomal instability, but initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. However, this concept has not been proven in vivo since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis (i) in a novel mouse model of inducible telomere dysfunction on a telomerase-proficient background, (ii) in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and (iii) in wild-type mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation and cancer cell proliferation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell cycle arrest and apoptosis in telomerase-deficient liver tumors. Together, these data provide the first in vivo evidence that transient telomere dysfunction during early and late stages of tumorigenesis can promote chromosomal instability and carcinogenesis in telomerase-proficient mice in the absence of additional genetic checkpoint defects at germline level.
2012-03-31 | GSE36813 | GEO
Project description:DNA replication is a complex process tightly regulated to ensure faithful genome duplication, and its perturbation leads to DNA damage and genomic instability. Replication stress is commonly associated with slow and stalled replication forks. Recently, accelerated replication has emerged as a non-canonical form of replication stress. However, the molecular basis underlying fork acceleration is largely unknown. Here we show that mutated HRAS activation leads to increased topoisomerase 1 (TOP1) expression leading to aberrant replication fork acceleration and DNA damage by decreasing RNA-DNA hybrids or R-loops. In these cells, restoration of TOP1 expression or mild replication inhibition rescues the perturbed replication and reduces DNA damage. Furthermore, TOP1 or RNaseH1 overexpression induces accelerated replication and DNA damage, highlighting the importance of TOP1 equilibrium in regulating R-loop homeostasis to ensure faithful DNA replication and genome integrity. Altogether, our results reveal a novel mechanism of oncogene-induced DNA damage induced by aberrant replication fork acceleration.
2022-09-08 | GSE168738 | GEO
Project description:Hoxa13 overexpression drives chromosomal instability and liver tumorigenesis in mice
| PRJNA700569 | ENA
Project description:Background and aims: Class I Homeobox (HOX) genes are fundamental components of embryonic patterning and morphogenesis, also implicated in neoplastic transformations. Among them HOXA13, in particular, has been found to be the most overexpressed in HCC and to be associated with worse prognosis. However, no previous work has shown so far a direct causal effect between HOXA13 overexpression and liver tumorigenesis. In this study we aimed to prove the direct oncogenicity of HOXA13 in the liver and to unravel the molecular mechanisms of Hoxa13-induced liver tumorigenesis. Approach and Results: To unravel the oncogenic mechanism of HOXA13 in vivo, a transgenic mouse model of HOXA13 overexpression in the liver was generated using hydrodynamic tail vein injection coupled with a transposase system. The mice phenotype was followed over time, from 2 weeks up to 1-year post injection. RNA-sequencing was performed to monitor the transcriptomic changes over time. HOXA13-overexpression in the liver led to highly proliferative hepatocytes and correlated with the DNA damage marker yH2AX. 1-year post-injection 50% of the injected mice developed liver tumors of various histological grades and types. RNA-sequencing analysis performed on whole liver extracts of 2 weeks-old mice and tumors showed that the main pathway deregulated by HOXA13 overexpression was cell cycle, in particular G2/M transition and mitotic spindle assembly checkpoint. Additionally, HOXA13-overexpressing livers showed a transcriptomic signature of chromosomal Instability, suggesting a possible mechanism of tumorigenesis driven by genome instability. Conclusions: Our study highlights the role of HOXA13 as a novel oncogenic driver in hepatocarcinogenesis and strongly suggests that its oncogenic properties are least partially mediated by induction of chromosomal instability.
2021-02-09 | GSE166341 | GEO
Project description:Chromosomal instability (CIN) is thought to be a source of mutability in human cancer. However, CIN is highly deleterious for the cell, and the resulting aneuploidy induces metabolic stress and compromises cell fitness. Here we utilized the X-chromosome dosage compensation mechanism and changes in X-chromosome number to demonstrate in Drosophila epithelial cells the causal relationship between CIN, aneuploidy, gene dosage imbalance and tumorigenesis. Whereas the harmful effects of CIN can be buffered by resetting the X-chromosome dosage compensation to compensate for changes in X-chromosome number, interfering with the mechanisms of dosage compensation suffices to induce tumorigenesis. In addition, multiple mechanisms buffer the deleterious effects of CIN including DNA-damage repair, activation of the p38 signalling pathway, and induction of cytokine expression to promote compensatory cell proliferation. These data reveal a key role of gene dosage imbalances to CIN-induced programmed cell death and tumorigenesis and the existence of robust compensatory mechanisms.
2016-05-23 | GSE71242 | GEO
Project description:Genomic instability is a common feature found in cancer cells. Accordingly, many tumor suppressor genes identified in familiar cancer syndromes are involved in the maintenance of the stability of the genome during every cell division, and are commonly referred to as caretakers. Inactivating mutations and epigenetic silencing of caretakers are thought to be the most important mechanism that explains cancer-related genome instability. However, little is known of whether transient inactivation of caretaker proteins could trigger genome instability and, if so, what types of instability would occur. In this work, we show that a brief and reversible inactivation, during just one cell cycle, of the key phosphatase Cdc14 in the model organism Saccharomyces cerevisiae is enough to result in diploid cells with multiple gross chromosomal rearrangements and changes in ploidy. Interestingly, we observed that such transient inactivation yields a characteristic fingerprint whereby trisomies are often found in small-sized chromosomes and gross chromosome rearrangements, often associated with concomitant loss of heterozygosity (LOH), are mainly detected on the rDNA-bearing chromosome XII. Taking into account the key role of Cdc14 in preventing anaphase bridges, resetting replication origins and controlling spindle dynamics in a well-defined window within anaphase, we speculate that its transient inactivation causes cells to go through a single mitotic catastrophe with irreversible consequences for the genome stability of the progeny.
2015-05-05 | GSE68530 | GEO